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Incidence of Heparin-Induced Thrombocytopenia and \"Argatroban\" Dollars At University Hospital In The United States

Background: According to published medical literature, there is variable incidence of heparin-induced thrombocytopenia (HIT), a life-threatening pro-thrombotic state, complicating unfractionated heparin (UFH) or low-molecular weight heparin (LMWH) use with immunogenic activation cascade evolving into arteriovenous thromboembolism.
Objective: To quantify incidence of suspected and/or confirmed HIT at our university hospital in the United States (US).
Materials and Methods: Presuming suspected/confirmed HIT whenever argatroban was used during the five year period (2009-2013), the argatroban usage patient lists were tabulated through our institutional pharmacy database. Subsequently, all these patients' electronic medical records were accessed to tabulate the final list of those patients wherein the presence of platelet factor 4 antibodies (PF4A) were tested based on the suspicion of HIT, and/or serotonin release assay (SRA) was used to further confirm HIT among patients with positively present PF4A. Simultaneously, the overall usage of UFH and LMWH at our hospital were assessed through our institutional pharmacy database to provide the denominator for calculating the incidence of HIT in our university hospital during the five year period.
Results: Over a five-year period (2009-2013), UFH and/or LMWH were administered to patients during 64,250 unique admissions while argatroban was administered to patients during 90 unique admissions over the same period. Among those 90 admissions, patients were tested for suspected HIT during 64 admissions only wherein presence of PF4A presumptively confirmed incidence of HIT during 18 admissions only. Only two patients were truly confirmed as SRA-positive HIT patients with one of them expiring during the hospital stay (50% mortality). During 64 admissions where HIT was suspected, the total argatroban costs incurred by the hospital was 142,809 US Dollars and the total argatroban charges levied on the patients/third-party-payers was 1,183,669 US Dollars.
Conclusions: The presumed incidence of HIT based on PF4A confirmation was at least 2 admissions among every 10,000 admissions receiving UFH and/or LMWH while the true incidence of HIT based on SRA positivity was at least 3 admissions among every 100,000 admissions receiving UFH and/or LMWH. Each admission during the five-year period where UFH and/or LMWH was used had an additional hospital cost of at least 2.22 "argatroban" US Dollars with patient/third-party-payer charge of at least 18.42 "argatroban" US Dollars as a reflection of our institutional economic burden secondary to suspected/confirmed HIT among our patient admissions.

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Relative Stoichiometry and Affinity for Describing Von Willebrand Factor Binding of Coagulation Factor VIII

The von Willebrand Factor (vWF) is the biggest multimeric protein in the body and plays an important role in hemostasis. Its main functions are to bind to collagen, to platelet GPIb and to coagulation factor VIII (FVIII). Von Willebrand Disease (vWD) is the most common bleeding disorder in the Caucasian population. If, as a qualitative defect, a variant vWF protects FVIII less than normal, not only the adhesion but also the formation of the clot is affected. This type of diseases is called vWD type 2Normandie (2N) and it cannot be identified by an aberrant multimeric pattern. Using  the published home made [1-7] ELISA assays on the vWD Type 2N as well as one commercially available assay [8-9], it is not possible to determine the stoichiometry or the affinity of the interaction, which would make it possible to classify and to correlate the variant regions of the vWF-molecule with functional features. Furthermore, it is complicated to perform the home-made assays, because two ELISA plates have to be processed in parallel. To replace the ill-defined term “binding capacity” by terms of classical biochemical meaning, namely the number of binding sites and the affinity of the binding, a simple method has therefore been developed combining the advantages of both techniques, namely biochemical clarity of the results and technical straightforwardness to determine the relative stoichiometry and affinity of the vWF interaction with FVIII, which can be carried out on one ELISA plate.

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http://www.webmedcentral.com/article_view/3949

Prognostic Significance of BMI1 Gene in Chronic Myeloid Leukemia Patients

BMI1 is a polycomb group (PcG) proteins which maintain self-renewal of stem cells, and is overexpressed in leukemia. This study was aimed to investigate the expression of BMI1 chronic myeloid leukemia (CML) and its clinical significance. Expression levels of BMI1 in 45 CML patients and 10 healthy controls were measured by real time quantitative polymerase chain reaction (RQ-PCR). The results showed that the expression of BMI1 was significantly higher in advanced phase than in chronic phase (p <0.05) and healthy controls (p <0.05). The 3-year survival rate was significantly lower in advance patients than in chronic phase CML patients (95% vs. 50%, p = 0.005). Interstingly, overall survival was longer in low BMI1 expression patients than in high BMI1 expression patients (p = 0.012). We conclude that detecting BMI1 is helpful for the diagnosis and prognosis by predicting the overall survival and monitoring of patients with CML.

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http://www.webmedcentral.com/article_view/3893

Detection of a Point Mutation at Codon 12 of the Kirsten-Ras (K-ras) Oncogen in Myelodysplastic Syndrome

Mutations in ras genes have been observed in a variety of cancers and were found to play an important role in human leukemogenesis and in preleukemic disease as myelodysplastic syndrome (MDS). The purpose of this study was to determine the prevalence of mutated K-ras oncogene in 30 patients suffering of myelodysplastic syndrome (MDS); with a special emphasis on their possible role in affecting clinical status, relation to karyotypic pattern; response to therapeutic measures; its impact on the fate of the disease and overall survival. The detection of point mutation in Kirsten-ras (K-ras) gene was performed by quantitative enriched polymerase chain reaction (QEPCR) and was confirmed by sequencing. QEPCR is a two- stage PCR procedure with modified primers that enriches mutant alleles, via restriction endonuclease digestion of normal alleles and enables identification of one mutant allele among 100,000 normal alleles. Activating mutations of the codon 12 of K-ras gene were detected in 7/30 (23.3%)cases of MDS, the most common mutation involved a substitution of aspartic acid for glycine (GGT?GAT). The incidence of K-ras mutations was found to be significantly associated with refractory anemia with excess blasts type II (RAEBII) and unclassified (UC) MDS than other subtypes (p=0.005), and was significantly associated with hypercellular bone marrow (p=0.04) showing marked dyserythropoitic changes. Furthermore, mutant K-ras gene was found to be significantly associated with abnormal karyotypes (p=0.04). Patients with mutated K-ras gene were significantly associated with either high or intermediate risk according to International Prognostic Scoring System (IPSS) (p=0.001). 6/7(85.7%) of those carrying the mutation showed poor response to treatment compared to non carriers with a statistical significant difference (p=0.009). Five out of eight (62.5%) patients who were transformed to AML carried the mutant K-ras gene, their subtypes were RAEB?? and unclassified MDS with abnormal cytogenetics mainly Monosomy 7. Overall survival was detected using Kaplan-Meier curve and the mean survival time of patients who carried K-ras mutations were significantly lower than those without the mutation (Log rank test=12.7; p=0.0004). In conclusion, MDS patients bearing an mutated K-ras oncogene frequently showed poor response to treatment; leukemic progression of the disease and shorter overall survival, suggesting that an activated K-ras oncogene is a critical factor for prognostic evaluation; therapeutic decision and monitoring of response to treatment of MDS patients.

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http://www.webmedcentral.com/article_view/3357

A Novel Approach to Treating FVIII Inhibitors: In Vitro Results for Combination Therapy with Human Prothrombin Complex Concentrate and Plasma-Derived FVIII/VWF Complex

Coagulation factor VIII (FVIII) inhibitors are the most severe complications of haemophilia A treatment. We studied the effect of a non-activated prothrombin concentrate (PCC) combined with FVIII in vitro. FVIII antibodies minimised the in vitro thrombin generation of standard human plasma and prolonged the lag phase at a residual FVIII activity of ≤ 0.01 IU/ml. Time to clotting of FVIII-inhibited fresh whole blood was not measurable until 55 minutes (observation time). Combining a PCC and a plasma-derived FVIII/VWF concentrate normalised TG and ROTEM® parameters. Our findings support an approach to moderately shift the haemostatic balance to a more procoagulant potential.

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http://www.webmedcentral.com/article_view/2444